Winter 2008

Visible Darkness

By bringing to light the biological basis of depression, researchers across the University are on a quest to personalize treatment and alleviate anguish

By Mary J. Loftus

Depressed rats—or, at least, rats that have been bred over several generations to exhibit depressed behavior—act in ways that are remarkably similar to clinically depressed people.

They isolate. They move more slowly. They sit in a corner of the cage instead of exploring. They aren’t as quick at cognitive tasks. They show little interest in food or sex.

As animal models go, this is about as good as it gets. Still, researchers are hesitant to claim that the rats actually are depressed.

“Depression is a complicated disorder,” says Assistant Professor Kerry Ressler, a researcher at Yerkes National Primate Research Center. “We are at a point with psychiatric disorders where medicine was a hundred years ago when, say, doctors diagnosed a ‘swollen leg.’ There are probably twenty different subdisorders that have a common pathway we call ‘depression.’ ”

To define the malaise of depression by a constellation of physical symptoms seems reductionist, even simplistic. Some of the best minds in the world, in expressing their own struggles with depression, crafted metaphors that capture the near-existential nature of the disorder: Vincent Van Gogh’s deep, dark well, Winston Churchill’s black dog, Sylvia Plath’s bell jar, William Styron’s “darkness visible . . . the despair beyond despair.”

Once Emory researchers enter their labs, however, they leave the world of metaphysical speculation for a more measurable universe of fMRIs, gene sequences, and C-reactive protein levels.

And these depression studies—taking place at Emory and other top research institutions around the country—are discovering specific correlates to depressive illness on all fronts: neurological, molecular, genetic, and behavioral.

Advances developed through depression research are sure to have far-reaching implications. Major depressive disorder is the most common of all psychiatric disorders. As many as 10 percent of Americans are diagnosed with clinical depression annually, and roughly 9 percent of men and 22 percent of women will have at least one episode of severe depression in their lifetime. Suicide accounts for more deaths each year than homicide or AIDS, according to the National Institute for Mental Health (NIMH).

Thomas Insel, former director of Yerkes and current director of the NIMH, states in his most recent budget report to Congress that his agency’s priority is to support research that identifies the biological basis of mental disorders to more precisely pinpoint targets for prevention and treatment. “This means understanding the neural basis of the illness at all levels,” he says.

Insel points to several recent groundbreaking studies on depression that found:

The formation of new neurons might be hindered in those with depression, and antidepressants are in part effective because they help stimulate neuron production.

Several genes have been implicated in susceptibility to schizophrenia and depression.

A gene variant that is especially common in people with depression is associated with a higher level of brain activation in response to threat or stress.

An explosion of research on the physiology of depression is providing hope that the disease can be treated more effectively. While the current best available treatment—a combination of antidepressants and psychotherapy—works for just half of those with depression, a new era in defining, typing, and treating depression is at hand. The goal is to create personalized therapies based on individual subtypes of depression.

Some Emory researchers study depression itself, while others come at it through corresponding disorders or emotions—fear, anxiety, post-traumatic stress, inflammation, heart disease, epilepsy. Special populations with depression are being considered by Emory researchers as well, including children, teenagers, veterans, new mothers, octogenarians, and adults who have been abused as children.

Studies have shown the risk of developing depression to be about one-third genetic, two-thirds environmental.

Experiencing trauma or abuse as a child raises the likelihood of having depression as an adult, especially in individuals with a genetic vulnerability. During this tender, formative time when the young body’s stress response axis is being created, it seems it can also become skewed—calibrated at too sensitive a point.

“These genetic predispositions and environmental influences likely act upon the neural circuits that mediate stress and fear responsiveness and affect modulation,” wrote Ressler and colleague Charles Nemeroff in a recent research review on the physiology of depression and anxiety disorders. “With sufficient stress, these systems likely shift to a dysregulated state leading to increased stress and fear responsiveness.These hypersensitive limbic pathways likely lead to experiences of defeat, anxiety, anger, negative mood, and aggression.”

Of body and brain

Nemeroff, the Reunette W. Harris Professor and chair of the Department of Psychiatry and Behavioral Sciences, has focused his latest research on the relationship of depression to illnesses such as cardiovascular disease.

“Depression is a systemic illness not just of the brain, but of the body,” says Nemeroff, who maintains a clinical practice as a psychiatrist ten hours a week and has treated such high-profile clients as CNN founder Ted Turner, former L.A. Times publisher Tom Johnson, and Atlanta business executive and philanthropist J. B. Fuqua for depression.

“There are peripheral manifestations of depression as well as behavioral and neurological ones. It puts people at risk of developing other diseases. In fact, the American Psychiatric Association now includes depression as a risk factor for the development of heart disease. It increases the risk of myocardial infarction, congestive heart failure, hypertension . . . depression is as significant a risk factor as cigarette smoking.”

People with depression are more likely to have blood clots, heart rate variability, chronic inflammation, and a decrease in bone density.

“Depression kills thirty thousand Americans a year by suicide,” says Nemeroff, who in December was named president of the American Foundation for Suicide Prevention. “But it kills many more through heart disease, stroke, diabetes, and the fact that depressed people are less likely to seek help for medical diagnoses and to adhere to medical treatments.”

In the next fifty years, he says, several breakthroughs can be expected.

“Identifying gene variants that confer vulnerability will result in the emergence of a new field: preventive psychiatry,” said Nemeroff, who along with other Emory researchers presented his findings to the Dalai Lama at the October 20 conference Mind and Life XV: Mindfulness, Compassion, and the Treatment of Depression. “Elucidating the causes of mental illness will lead to novel treatments. We will also see breakthroughs in understanding the biology of resilience, now poorly understood. And in contrast with our largely trial-and-error based system, treatments will be individualized, based on genomics and brain imaging.”

The smell of fear

Kerry Ressler’s research begins where such work usually begins: in a room with small rodents.

Ressler, an amiable, soft-spoken scientist who studies fear, was recently named one of fifteen new Howard Hughes Medical Institute Investigators—considered to be the nation’s top physician-scientists who will ensure that basic research discoveries are translated into improved treatments for patients. He is the first practicing psychiatrist to gain such a designation.

“The fear response in a mouse is the same as in a human, so we understand the circuitry,” he says, walking down a flight of stairs from his bright, airy office to his dark, cloistered lab. “The areas of the brain involved in emotional learning and expression are similar across mammals from mice to men.”

Overactivation of the amygdala— an almond-shaped mass of neurons in the brain’s limbic system—has been implicated in depression and anxiety disorders. “It’s not the thinking, executive brain that’s involved, it’s the old, emotional parts that get out of control,” he says. “More and more things we see as pathology are actually evolved brain systems in habit formation.”

Fear, Ressler believes, is intimately linked to depression and other mood disorders, especially those that stem from traumatic experiences or stress-response conditioning. And because it is an instinct, fear can easily be taught to rodents using conditioning.

Ressler sometimes conditions mice to be afraid of specific odors. The sense of smell has proven to be a very powerful emotional trigger, since it tends to bypass the higher-functioning, cognitive processing areas of the brain.

“Odors are one of the most salient cues for being afraid, in mice or humans,” he says. “In working with Iraq veterans, there is a fear response to the odor of burned tires. With Vietnam veterans, it’s rice or rain.”

What was once a beneficial reaction—an appropriate fear response to an external stimulus signaling danger—got “stuck” and now can’t be mediated, as in post-traumatic stress disorder.

This maladaptive response occurs in depression, too, Ressler reasons. Everyone gets sad; everyone has bad days. “But depression is a bad day gone a hundred-fold over the top that can’t be turned around,” he says. “Depression can be cyclic and spiraling.”

Ressler’s research into the molecular biology of fear already has had a therapeutic impact. With colleagues Michael Davis and Barbara Rothbaum, Ressler has developed a treatment that has proven successful for anxiety-related disorders like fear of heights and social anxiety disorder. They discovered that using d-cycloserine (DCS), a drug originally developed for tuberculosis, in combination with exposure-based psychotherapy diminished the underlying fear response more rapidly than psychotherapy alone.

The first clinical trials were so encouraging that more than ten additional clinical trials are under way to examine the effect of DCS on post-traumatic stress disorder and other anxiety and fear-based disorders.

Ressler, who is codirector of the Post-Traumatic Stress Disorder (PTSD) program at Grady Memorial Hospital in Atlanta, has expanded clinical trials to include both war veterans and inner-city residents in Atlanta who have been traumatized by exposure to violence.

“We’ve taken complete histories—medical, pharmacological, trauma, and abuse history—of 1,200 people, and our goal is three to four thousand,” he says. “Early findings are that the rates of PTSD in this highly impoverished, minority population is about 20 to 30 percent—as high as for Vietnam vets. Sixty percent have been attacked with weapons, 30 percent of the women have been sexually assaulted. About half personally know someone who’s been murdered.”

Rates of depression in this group can be as high as 30 percent—much higher than in the general population.

Ressler’s research illustrates how life events and genetic influences can combine in complex ways, leading to depression or protection from it. “We know that childhood abuse and early life stress are among the strongest contributors to adult depression. Research can ultimately help us learn how we might be able to better intervene against the pathology that often follows.”

Epileptics and melancholics

At least one physical illness has long been associated with depression: epilepsy. In the fourth century BCE, Hippocrates noted that “melancholics ordinarily become epileptics, and epileptics, melancholics.” While this link has been anecdotally observed, however, research has been scant.

Assistant Professor David Weinshenker of the Department of Human Genetics uses genetic models combined with pharmacological tools to study such questions as whether depression and epilepsy are associated, how antidepressants work, and other aspects of neurobiology.

“Doctors used to think, well, of course patients with epilepsy are depressed—they have a serious physical illness and are depressed about it. But it ended up to be bidirectional—people with a history of depression, or a family history of depression, were more likely to get epilepsy as well. This led us to believe that they share some of the same underlying mechanisms.”

Weinshenker, ensconced in an office in the Whitehead Biomedical Research Building decorated with bright artwork by his two sons, has focused his studies on norepinephrine (NE)—one of the most abundant neurotransmitters in the central and peripheral nervous systems.

“NE is best known for controlling aspects of the sympathetic nervous system, including regulation of cardiovascular function and energy metabolism,” he says. “However, it also has profound effects on brain regions that control mood and seizures. Because NE in the brain is both an antidepressant and anticonvulsant, we hypothesize that a loss of NE could contribute to both epilepsy and depression.”

Weinshenker and colleagues are currently attempting to create animal models of epilepsy and depression interaction. They are testing seizure susceptibility in rats bred for depression-like behavior, and for depression-like behavior in epileptic rodents. They also are studying mice that have been genetically altered to completely lack norepinephrine, to assess the contribution of NE to the comorbidity of these diseases.

Doctors still commonly treat epilepsy as the primary illness and depression as secondary, Weinshenker says—that is, if they deal with the depression at all. But, he notes, if you ask people with epilepsy how they are faring, their quality of life depends more on the status of their depression than on the status of their epilepsy.

“So it’s incredibly important to treat the depression, not just to ignore it and treat the epilepsy because it is the ‘physical’ illness,” he says. “To complicate matters, there are antiepilepsy drugs that can cause depression, and anti-depressants that can cause seizures. It’s a juggling game to treat one without making the other worse. There is no first-line treatment for both.”

It’s important, Weinshenker says, to evaluate the effects of both conventional and new antidepressant therapies on seizure susceptibility.

His hope is that advances in the treatment of both illnesses may finally break the long-standing link between epilepsy and melancholia.

Soothing an inflamed immune system

To find Andrew Miller’s office, walk up the staircase of the Winship Cancer Institute, past the floors labeled “Courage,” “Hope,” “Imagination,” and “Translation,” to “Discovery”—a suite of labs and offices devoted to collaborative research. Dry erase boards between doors in the hallway are filled with formulas, quotes, and recent findings.

“I’m somewhat off the beaten path in that we are one of the pioneering groups exploring the role of the immune system in depression,” Miller says.

When the innate immune response becomes activated, often due to illness or injury, Miller says, it releases cytokines, which can get into the brain and change its chemistry and the functioning of the neuroendocrine system.

The discovery that stress itself, in absence of actual harm or injury to the body, could turn on the innate immune response, was “when things became exciting,” Miller says. “This opens up a whole series of new treatments for depression that target the immune system.”

Inflammation, he says, is now seen as a common mechanism for many diseases, from heart disease to diabetes, and perhaps cancer.

But it is the connection between inflammation and depression that fascinates Miller, with its potential for novel treatments. Measuring an individual’s inflammation levels is as simple as taking a blood test, he says: C-reactive protein (CRP) is a key indicator. A CRP of about three indicates inflammation at a clinically significant level; above ten indicates infection or autoimmune disease.

“CRP levels provide a biomarker, which is a key step toward individualized therapy,” he says. “Doctors could measure someone’s CRP levels like they measure triglyceride levels or cholesterol levels.”

Stressors that cause inflammation can be psychological or social—demanding jobs, difficult relationships, poverty, physical threats, war, natural disaster. Physical stressors such as illness or injury also raise CRP levels and should be ruled out before psychosocial stressors are identified as the cause, Miller says.

Emotional and physical stressors such as abuse and neglect early in life can also create chronically elevated CRP levels, he says. “Chronic stress causes the body to adapt and to run inflammation at higher levels,” Miller says. “The body is sensing that the environment is unpredictable or unsafe, and that it could be physically injured or attacked at any time. This causes the immune system to be on red alert.”

Antidepressants seem to have some effect on the immune system, at least in the lab, although systems that target inflammation directly may be the way to go in the long run, says Miller.

There is a downside, however: “Because these treatments may leave people vulnerable to infection, they have a more significant risk. We would probably start with depressed patients who are resistant to standard antidepressant treatment.”

Since reducing stress would be the ultimate prevention, Miller says, drugs need not always be the answer.

“You can ease stress with exercise, meditation, yoga . . . even acute stress, like watching a scary movie or riding a roller coaster, reduces chronic stress,” he says. “When something is exciting or exhilarating, it stresses you in a good way.”

Miller sees these stress-busters as “soothing interventions for a hot, inflamed immune system.”

Putting the pieces together

Neurologist Helen Mayberg compares her research on the brain to trying to put together “a large jigsaw puzzle where all the pieces are in the box, but there is no picture. You may have a section of pieces that fit together. But don’t throw away the pieces that don’t fit, because after a while, a pattern starts to emerge.”

While leading theories of depression focus on psychological or biochemical causes, Mayberg has spent two decades investigating the specific brain regions that mediate mood and emotions. “Certain regions seemed especially critical,” she says. “These findings provided the foundation for a new approach to treating depression—directly modulating these circuits using deep brain stimulation.”

The first study using deep brain stimulation to treat depression, led by Mayberg, a professor in the Departments of Psychiatry and Neurology, with former colleagues at the University of Toronto, provided encouraging evidence that deep brain stimulation surgery can help some intractably depressed patients in dramatic ways.

It can take months for patients to respond to antidepressants or psychotherapy. Electroconvulsive therapy (ECT) is effective in about 60 percent of remaining cases, but these patients have a high relapse rate—50 percent over six months.

So Mayberg and her team were stunned when some deep brain stimulation patients reported an immediate and spontaneous lifting of their symptoms. Even more promising, more than half of the patients emerged from their depression and remain well four years later.

Now Mayberg is replicating and expanding the deep brain stimulation study at Emory, with principal psychiatrist Paul Holtzheimer and neurosurgeon Robert Gross, using a wider array of patients.

Deep brain stimulation involves the constant stimulation of a specific brain circuit. Patients are awake and alert even at the time of implantation and first testing. It has been used to treat a variety of neurological disorders including epilepsy, Parkinson’s, and dystonia, but never—until now—depression.

The key to deep brain stimulation is determining the optimal site to stimulate. Depressed patients show no obvious brain abnormalities on tests such as MRIs to guide such target selection, says Mayberg. Like many psychiatric disorders, depression is thought to result from complex interactions among genes, stress, chemistry, and brain circuitry.

Mayberg and her colleagues, however, decided to focus on a particular brain region—the subcallosal cingulate, also called Brodmann Area 25—that seems to play a critical role in regulating negative moods in both healthy and depressed individuals.

Her team implanted thin wire electrodes in patients’ brains in this area; the other end was connected to an implanted pulse generator that directed the electrical current. Four of the first six patients—who had not responded to any other form of treatment—completely emerged from their depression. In fact, several deep brain stimulation patients reported a visceral response, experiencing an abrupt shift in perception in the operating room.

“Patients described a sudden disappearance of something negative: a sense of intense calm and relief, a clearing of mental heaviness, the disappearance of a void, the fading of a burrowing dread in the pit of the stomach,” says Mayberg. “Getting sad is not abnormal; staying sad no matter what is going on around you is—and we call that depression. The goal with deep brain stimulation is not to prevent sadness, but to allow patients to experience appropriate sadness without getting stuck.”